tbuckley/cabot-search huggingface dataset:
Phase 2 study to assess the efficacy, safety, and tolerability of the GDF-15 inhibitor ponsegromab in patients with cancer cachexia.
Authors: Jeffrey Crawford, Shannon L Lubaczewski, Anil Tarachandani, Magdalena A Harrington, Yan Weng, Ruolun Qiu, Susie M Collins, Michelle I Rossulek, James H Revkin
Journal: Journal of Clinical Oncology (2023)

TPS12147 Background: Cancer cachexia is a multifactorial metabolic syndrome of wasting characterized by anorexia, unintended weight loss, and decreased skeletal muscle mass, leading to progressive functional impairment, fatigue, diminished quality of life, poor response to anticancer therapy, and reduced survival. One of the biomarkers associated with cancer cachexia is cytokine growth differentiation factor 15 (GDF-15), which is secreted by tumor cells. Preliminary phase 1 data suggest that suppression of GDF-15 may lead to improvement in cachexia-related symptom burden. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signaling. The primary objective of this study (NCT05546476) is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia, and elevated circulating GDF-15 concentrations. Secondary objectives include assessing physical activity, gait, anorexia/appetite, nausea and vomiting, fatigue, and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, and immunogenicity. Methods: This phase 2 study will enroll approximately 168 adults with non–small cell lung, pancreatic, or colorectal cancers who have cachexia and elevated GDF-15 concentrations. The study will be conducted in 2 parts. The initial 12-week treatment period will be a randomized, double-blind, placebo-controlled study wherein participants who meet eligibility criteria will be randomized 1:1:1:1 to one of 3 dose groups of ponsegromab (administered subcutaneously [SC] every 4 weeks [Q4W]) or placebo. The double-blind period will be followed by optional open-label treatment (OLT) with ponsegromab Q4W SC for up to 1 year. Upon completion of the optional OLT period, there will be a follow-up visit at Week 72. Participants who do not proceed with the optional OLT period will complete the Week 12 visit and a follow-up visit at Week 16. The primary endpoint is the mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian E max model will be used for the primary analysis. Secondary endpoints include physical activity and gait measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy scores; anorexia/appetite, nausea, vomiting, and fatigue evaluated according to questions from the Cancer-related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs, and electrocardiogram abnormalities. © 2023 American Association for Cancer Research®. Reused with permission. Clinical trial information: NCT05546476 .
Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment.
Authors: Yue Zhou, JianJiao Ni, Zhengfei Zhu, Zhen Zhang
Journal: Journal of Clinical Oncology (2023)

2032 Background: Data on the efficacy of immune checkpoint inhibitors on delaying or preventing the occurrence of brain metastases (BMs) in metastatic NSCLC without initial BMs is limited. We explored the benefit of first-line atezolizumab versus chemotherapy in the occurrence of BMs in patients without baseline BMs. Methods: Individual patient data from IMpower1301, IMpower131, and IMpower150 were pooled. All patients in the intention to treat population were analyzed. Primary endpoints included BM free survival (BMFS) and the cumulative incidence of BM. Patients without baseline BMs were categorized into two groups: patients who received treatment including atezolizumab (atezolizumab group) and patients who received comparator chemotherapies (chemotherapy group). Results: In 2543 patients without baseline BMs, 87 (3.4%) developed BM, including 58 (3.4%) and 29 (3.4%) in the atezolizumab group and the chemotherapy group, respectively. The median BMFS was 8.31 months (95% CI 7.79-8.67). The cumulative incidence of BM at 6 months, 12 months, and 24 months was 1.9%, 3.1%, and 3.8%, respectively. Compared to the chemotherapy group, BMFS was significantly improved in the atezolizumab group (8.6 months versus 7.3 months, p &lt; 0.001). After taking the competing risk events into account, no significant difference of the cumulative incidence of BM was observed between the two groups ( p = 0.671), suggesting that the significantly better BMFS in the atezolizumab group analyzed by Kaplan-Meier method should be due to the lower incidence of extracranial progression or death. Baseline bone metastasis and non-squamous NSCLC were identified as two risk factors for BM. Conclusions: In patients with NSCLC without baseline BMs, first-line atezolizumab improved BMFS but not the cumulative incidence of BM compared to chemotherapy, indicating that atezolizumab could not reduce the intrinsic risk of intracranial tumor spreading. [Table: see text]
The perception of cervical cancer screening and prevention among Saudi women.
Authors: Atlal M. Abusanad, Lama Alharbi, Seham Alsalamah, Manal Almasary, Amnah Alharthi, Marwan R. Al-hajeili
Journal: Journal of Clinical Oncology (2023)

e17519 Background: Cervical cancer (CC) is the fourth cause of malignancy-related deaths among women globally. In Saudi Arabia, it is the 8th most prevalent cancer and the 7 th cause of cancer mortality among women between the ages of 15–44. There is a limited national data on the awareness of CC, human papilloma virus (HPV), and knowledge of screening and prevention. We present the largest national study to date investigating knowledge of Saudi women toward CC, the HPV vaccine, Pap smear, and influencing factors of their application. Methods: A structured questionnaire of 22 questions included demographic data, CC awareness and associated risk factors, evaluation of Pap-smear and HPV vaccine knowledge and their application was constructed and validated. Participants were exclusively female. It was distributed across the country and scored according to a pre-defined scoring system. Influencing factors of CC, Pap-smear and HPV vaccine knowledge and awareness were examined. A regression model to predict the possibility of performing Pap-smear was generated. P-value of 0.05 and less indicated statistical significance in all tests. Results: 2539 female participants completed the questionnaire with (41%) aged 18 - 25 years old. A sizable portion were from the central region (30.4%) and a majority had a university degree (73.1%). 65% of the participants were sexually active. Two thirds of the participants have heard about Pap-smear and its role in detecting CC but only 20% took the test. Although one third knew that the HPV vaccine can prevent CC, only 2% received the vaccination. Poor knowledge on locating the Pap-smear and HPV vaccine were reported among participants. 12% reported that health campaigns were their source of information. Factors associated with adequate knowledge are listed in table. Age predicted the possibility of performing Pap-smear with participants of 18 - 25 years old are more likely to take the test (P=0.00). Conclusions: This large study evaluated the knowledge and awareness of CC, Pap-smear, and the HPV vaccine across the country. It demonstrated the need for better advocacy and for a nation-wide campaigning to further utilize early detection and preventive procedures. [Table: see text]
Differences in racial and sex at birth representativeness between randomized controlled trial (RCT) and real-world evidence (RWE) or Surveillance, Epidemiology, and End Results (SEER) datasets in advanced non-small cell lung cancer (aNSCLC).
Authors: Kristin M. Zimmerman Savill, Danielle Gentile, Parisa Asgarisabet, Madison Brown, Dhruv Chopra, William S John, Richard Scott Swain, Andrew J. Klink, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2023)

e18654 Background: Historically, racial and ethnic minorities, women, and older patients have been underrepresented in RCTs. Hence, therapeutics are approved based on data not representative of the broader population, leaving important gaps in knowledge of safety and effectiveness. RWE may help address these gaps and inform regulatory, clinical, payer, and manufacturer decision-making. Racial, sex at birth, and age distributions were compared between RWE studies and a corresponding RCT in the aNSCLC setting. Additionally, RCT data were compared to SEER aNSCLC data. Methods: Demographics of adults with aNSCLC in the KEYNOTE-407 RCT were compared with those of adults in two physician-abstracted medical chart review US RWE studies conducted in 2019 or 2020 or with the most recently available US SEER data (2017-2019). Statistical comparisons were performed using t-tests or chi square tests. Results: We identified 10,089 patients (RCT: n = 559, 5.5%; RWE: n = 783, 7.8%; SEER: n = 8,747, 86.7%) (Table). Significant differences in racial distribution were observed between the RCT and RWE study populations, with Black/African American patients comprising 1.3% of RCT patients and 24.0% of the RWE study population. Non-Hispanic Black patients made up 12.8% of SEER patients. The proportion of female patients was lower in the RCT (18.6%) compared with RWE (40.5%) and SEER (36.7%) data. Age at 1L initiation was significantly lower for RCT patients vs. age at metastatic diagnosis in SEER (mean: 64.7 vs. 70.0 years). However, no statistically significant difference in age at 1L initiation was observed between RCT and RWE data (64.9 vs. 64.7 years). Conclusions: In aNSCLC, significant differences in sex at birth and race were observed between RCT and RWE study populations. Additionally, significant differences in sex at birth and age were observed between RCT and SEER data. Given that regulatory, therapeutic development, clinical, payer, and decision-making is largely driven by data from RCTs, future research can leverage RWE to improve representativeness and generalizability. [Table: see text]
Evaluating the diagnostic performance of leptomeningeal diagnosis with CNSide compared to standard cytology.
Authors: Haley Appel, Yazmin Odia, Anshul Saxena, Mukesh Roy, Alexander Mohler, Rupesh Kotecha, Matthew David Hall, Manmeet Singh Ahluwalia, Minesh P. Mehta, Serguei A. Castaneda
Journal: Journal of Clinical Oncology (2023)

2028 Background: Prior reports cited detection rates of leptomeningeal metastases (LM) using CNSide vs standard CSF cytology of 78% vs 55% in NSCLC and 84% vs 52% in various solid tumor cohorts. The objective of this study was to compare the real-world performance of the CNSide assay in diagnosing LM versus CSF cytology from lumbar puncture (LP) and established EANO-ESMD LM diagnostic criteria (EANO). Methods: We retrospectively analyzed all neuro-oncology patients from January, 2020 to December, 2022 with suspected LM who underwent LP with CSF cytology and CNSide. The CNSide assay included tumor cells (CSF-TCs) and cell-free DNA (cfDNA). LM diagnostic probability was defined by EANO criteria. Descriptive statistics and confusion matrix were calculated. Results: 87 patients (66 [76%] women) met eligibility criteria for inclusion with median age of 63 (23-87) years; 35 (40%) had uncontrolled systemic disease. The most common primary histologies were breast (45%) and lung (41%); 33% of primary lung cancers harbored molecular alterations, while primary breast cancers expressed hormone receptors in 69% and HER2 alterations in 10%. Across all primary histologies, 53 (61%) cases harbored molecular alterations, of which 27 (31%) had molecular alterations also detected by CNSide. For 7 (8%) cases with negative cytology and CNSide, CNSide detected alterations by cfDNA assays. LM was diagnosed by CSF cytology in 23 (27%) cases, consistent with confirmed LM by EANO. 36 (41%) cases had confirmed LM by CSF cytology or CNSide; all cytology positive and equivocal cases were detected by CNSide. Patients with negative CSF cytology were further defined as probable (19, 23%), possible (35, 42%), or (7, 8%) lack of evidence by EANO. Modifying EANO criteria to include both standard CSF cytology and CNSide led to 36 (41%) confirmed LM cases, an increase of 13 cases in addition to the 23 cytology positive cases (+56.5%). Compared to CNSide, standard CSF cytology had a sensitivity of 70%, but an expected 100% specificity. Compared to the established higher specificity of CNSide, EANO had 100% sensitivity, but only 18% specificity for diagnosing LM, assuming all EANO possible, probable, or confirmed cases were positive, while specificity improved to 74% with slight decrease sensitivity to 94% if only probable or confirmed cases were considered positive. Conclusions: In the largest, retrospective, single institution, real-world study, implementation of CNSide showed increased sensitivity relative to standard cytology and increased specificity relative to EANO criteria, and provided clinically relevant, cell-based molecular and cell-free DNA analyses. CNSide increased the diagnostic yield by 56.5%.
Association of somatic mutations and histologic subtype/grade on prognosis and PD-L1 expression in mesothelioma.
Authors: Allen Zhu, Aliya N. Husain, Andrew Hermina, Owen Mitchell, Jeffrey S. Mueller, Michael William Drazer, Hedy L. Kindler, Jung Woo Kwon
Journal: Journal of Clinical Oncology (2023)

8507 Background: Mesothelioma includes epithelioid, sarcomatoid, and biphasic histologic subtypes, and the epithelioid subtype is histologically graded based on mitotic count and nuclear atypia. Correlation between the most common somatic mutations ( BAP1, NF2, TP53, CDKN2A), and overall survival is poorly understood. High PD-L1 expression is a poor prognostic factor for survival and may be a predictor of response to immunotherapy. Few studies have evaluated the relationships between these factors. Methods: We performed a retrospective study in 217 patients with pleural, peritoneal and bicavitary mesothelioma as part of an IRB-approved biobanking protocol. Histologic subtype, grade of epithelioid mesothelioma, tumor stage, and overall survival time were determined. Next-generation DNA sequencing (NGS) was used to identify the prevalence of somatic mutations. PD-L1 immunohistochemistry was obtained on 184 samples and quantified as percentage of tumor cells. Histologic subtype, nuclear grade, clinical stage, PD-L1 expression, survival time, and the prevalence of each mutation were compared using chi-squared, Kruskal-Wallis, or Cox proportional hazard tests. All p-values were determined in R version 4.2.0 using a two-sided alpha error of 0.05 to mark statistical significance. Results: The most frequent somatic mutations were found in BAP1 (99/217, 45.6%), CDKN2A (47/217, 21.7%), TP53 (37/217, 17.1%), and NF2 (31/217, 14.3%). Patients with CDKN2A-mutated mesothelioma experienced shorter survival (p=0.032). TP53 mutations were associated with higher nuclear grade (p=0.015), higher mitotic count (p=0.013), and greater nuclear atypia (p=0.015). TP53 mutations were more prevalent in pleural than peritoneal mesothelioma (p=0.016) and in tumors without lymph node metastasis (p=0.05). As expected, patients with epithelioid mesothelioma had superior overall survival (p=0.02) and their tumors had lower PD-L1 expression (p=0.007) than either sarcomatoid or biphasic mesotheliomas. Neither PD-L1 expression nor mutations in BAP1, NF2, CDKN2A, or TERT were associated with nuclear grade, atypia, or mitotic count. No association was found between BAP1 or NF2 mutations and tumor stage, lymph node metastasis, or PD-L1 expression. Conclusions: To our knowledge, this is the first study of this scale to correlate PD-L1 expression, somatic mutation data, histologic features, and survival in mesothelioma patients. The most significant findings were that patients with CDKN2A mutations had shorter survival and TP53 mutations, which were more prevalent in pleural mesotheliomas, were associated with higher nuclear grade, higher mitotic count, and greater nuclear atypia. An ongoing analysis evaluates the contribution of germline mutations, which occurred in a significant proportion (15.7%) of this mesothelioma patient cohort.
Reduced symptom burden after implementation of an electronic symptom management program.
Authors: Jessica J Bian, Paige Ahrens, Angela Tramontano, Christine Cronin, Sandra L. Wong, Raymond U. Osarogiagbon, Hannah W. Hazard-Jenkins, Don S. Dizon, Roshan Paudel, Deborah Schrag, Michael J. Hassett
Journal: Journal of Clinical Oncology (2023)

12006 Background: The SIMPRO consortium implemented an electronic patient reported outcomes (ePRO) symptom management program as part of routine clinical care for patients (pts) receiving systemic cancer therapy or surgery across six health systems including rural and community cancer centers. To evaluate impact of the Epic-integrated electronic symptom management (eSyM) program on quality of life, pre- and post-implementation surveys were sent to a subset of gastrointestinal, thoracic, and gynecologic medical oncology (MO) and surgical (Surg) patients at all sites. Methods: A survey assessing symptom burden, health literacy, and self-efficacy was administered to separate groups of MO and Surg pts before (Pre-Implementation) and after (Post-Implementation) eSyM deployment. A waiver of documentation of consent was obtained for participation. Questions were derived from validated instruments including PROMIS, a standardized measurement tool for patient-reported symptoms. Surveys were completed 30-90 days after surgery or start of systemic therapy. PROMIS item responses were scored individually then translated into standardized T-scores with a mean of 50 based on an established reference population. Mean T-scores for PROMIS depression, anxiety, fatigue, and pain interference were calculated. Higher T-score correlated with greater symptom burden. Comparison between groups utilized non-parametric Kruskal-Wallis testing. Results: The number of survey responses were 498 MO Pre-Implementation, 518 MO Post-Implementation, 566 Surg Pre-Implementation, and 507 Surg Post-Implementation. MO pts reported significantly lower PROMIS mean T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of MO pts prior to eSyM. Surg pts reported lower T-scores for depression, anxiety, fatigue, and pain interference after eSyM compared to a similar group of Surg pts prior to eSyM, although reduction in pain interference was not statistically significant. Conclusions: eSyM deployment in MO was associated with a significant reduction in patient reported depression, anxiety, fatigue, and pain interference. Surgical pts after eSyM deployment reported significantly lower rates of depression, anxiety, and fatigue. External validation with PROMIS based surveys demonstrated small but meaningful benefits of ePRO symptom monitoring as part of routine clinical care across six diverse health systems. Clinical trial information: NCT03850912 . [Table: see text]
Ustekinumab for the treatment of immune related cutaneous adverse events (ircAEs).
Authors: Tara Maier, Stephanie Gu, Neil J. Shah, David M. Faleck, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2023)

e14702 Background: IrcAEs are one of the most common immune related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI). Ustekinumab, a monoclonal antibody that targets IL12/IL23, is FDA approved for the treatment of autoimmune diseases including psoriasis and inflammatory bowel disease. The IL12/23 pathway may mediate a subset of ircAEs, and ustekinumab may be effective for the treatment of these events. Methods: Patients at Memorial Sloan Kettering Cancer Center who received ustekinumab for treatment of ircAEs were identified from 8/18/2017 to 2/17/2022. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used to grade ircAEs. Patient response to ustekinumab was subcategorized into complete resolution (CR, improvement of symptoms to baseline or grade 0), partial resolution (PR, improvement in CTCAE grade but not CR), or no response/worsening (NR, no clinical improvement or worsening of ircAEs). Results: A total of 11 patients were included in the study. The median age was 72 years (IQR 69.5-77) and 45% of patients were female. The most common ICIs were pembrolizumab (64%, n=7), nivolumab (18%, n=2), atezolizumab (9%, n=1), and avelumab (9%, n=1). Melanoma (27%, n=3) and bladder (27%, n=3) cancer were the two most common neoplasms. All patients had psoriasiform ircAEs (n=10), except one who had a pyoderma gangrenosum (PG) ircAE; most were either grade 2 (46%) or grade 3 (36%) at the time of ustekinumab initiation. The majority of patients (73%, n=8), including the one with PG, noted some improvement with ustekinumab, with 55% (n=6) and 18% (n=2) achieving CR and PR, respectively. The median duration of ustekinumab treatment was 169 days (0 – 1774), and among those with PR or CR, the median time to initial response was 27 days (21 – 39). In addition, the proportion of patients on topical and systemic steroids before and after ustekinumab decreased from 91% (n=10) to 56% (n=6) and from 64% (n=7) to 36% (n=3), respectively. Four patients (36.4%) discontinued ICIs because of severe ircAEs, with 1 (25%) successfully recontinuing their ICI following control of ircAE symptoms with ustekinumab. We noted progression of disease among 55% (n=6) of patients at any point after ustekinumab treatment. Among them, median time to next treatment was 345.5 days (70-925), with a median of 347.5 days (70-576) and 601 days (277-925 days) for patients with non-metastatic (33.3%) and metastatic tumors (66.7%), respectively. Conclusions: Ustekinumab has shown encouraging clinical activity especially for psoriasiform ircAEs and can be an effective steroid-sparing treatment for specific ircAEs. Despite the occurrence of cancer progression in some of our cohort, it was difficult to interpret the ICI anti-tumor activity post ustekinumab given the small numbers and multiple tumor types. Further prospective studies are needed to validate our findings given the significant potential of ustekinumab for the management of ircAEs.